Refining method for industrially preparing nicardipine hydrochloride alpha crystal form

Abstract

The invention provides a refining method for industrially preparing a nicardipine hydrochloride alpha crystal form, and relates to the technical field of medicine refining. The refining method for industrially preparing the nicardipine hydrochloride alpha crystal form comprises the following steps: firstly, adding a nicardipine hydrochloride crude product into an acetonitrile solvent, and carrying out primary refining to obtain a nicardipine hydrochloride acetonitrile solvate crystal form; and secondly, adding the nicardipine hydrochloride acetonitrile solvate crystal form into an acetone solvent, and carrying out secondary refining to obtain a nicardipine hydrochloride alpha crystal form refined product. The refining method disclosed by the invention has the advantages of simplicity and convenience in operation, energy conservation and consumption reduction, short production period, good equipment compatibility, more suitability for industrial large-scale production and the like, the purity of the prepared nicardipine hydrochloride alpha crystal form reaches 99.7% or above, any single impurity is less than 0.10%, the yield reaches 90% or above, and the refining method has practical popularization and application values.

Description

Technical Field

[0001] The present invention relates to the technical field of drug purification, and particularly to a purification method for industrially preparing α-crystal form of nicardipine hydrochloride. Background Art

[0002] Nicardipine hydrochloride (NHc) is an L-type dihydropyridine calcium channel antagonist, which has the characteristics of high selectivity, low cardiac toxicity and good efficacy. It is widely used in the clinical treatment of hypertension and angina pectoris, and is one of the first-choice drugs for lowering blood pressure. The chemical name of NHc is 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid-2-[methyl(benzyl)amino]ethyl methyl ester hydrochloride, and its structural formula is as follows:

[0003]

[0004] It is reported in the literature (Mol. Pharmaceutics 2011, 8, 395–404) that there are five crystal forms of nicardipine hydrochloride, namely α-crystal form, β-crystal form, dihydrate, toluene compound and chloroform compound. Among them, the melting points of the α-crystal form and β-crystal form are measured by a melting point apparatus, which are 179–188 °C and 164–171 °C respectively. The NHc preparation was first developed in Japan and then marketed in the United States and Europe. According to the drug specifications of NHc preparations marketed in Japan, the United States, Europe, etc., the melting points of the raw materials used are all 169–171 °C, indicating that the original research products are all β-crystal form raw materials. China includes NHc raw materials in the Chinese Pharmacopoeia, but the recorded melting point is 179–185 °C. However, the above literature does not report the purification and impurity removal effects and yields of the products.

[0005] After retrieval, there are few reports on the purification of nicardipine hydrochloride at present. Among them, Patent 1 (CN117032483) discloses a purification method of nicardipine hydrochloride, which hydrolyzes nicardipine hydrochloride under alkaline conditions to remove impurities, but increases the risk of product degradation during hydrolysis, which is not conducive to product quality control.

[0006] Patent 2 (JPH03240773A) discloses a purification method of nicardipine hydrochloride. The method is to first heat and dissolve the crude product of nicardipine hydrochloride in methanol, then distill off methanol under reduced pressure, and add acetone to the residue for crystallization to obtain the finished product of nicardipine hydrochloride. This method requires distilling off methanol under reduced pressure in a crystallization tank, and its operation is relatively cumbersome, especially not suitable for industrial production.

[0007] In summary, the problems existing in the reported purification methods of nicardipine hydrochloride in the prior art are as follows: for example, the steps of removing impurities will also increase the risk of product degradation, presenting certain quality risks; the steps are cumbersome and not convenient for operation, and are not suitable for industrial production; therefore, it is still a problem to be solved at present to research and find a purification route with reliable product quality and safety, simple operation, short production cycle, good equipment compatibility, and more suitable for large-scale industrial production. Summary of the Invention

[0008] To overcome the above technical defects, the object of the present invention is to provide a new purification method for the industrial preparation of α-crystal form of nicardipine hydrochloride. This method solves the problems of quality risks, cumbersome steps, inconvenient operation, and inapplicability to industrial production existing in the prior art, and realizes reliable quality and safety, simple operation, short production cycle, good equipment compatibility, and more suitability for large-scale industrial production.

[0009] For this purpose, the present invention provides a purification method for the industrial preparation of α-crystal form of nicardipine hydrochloride, comprising the following steps:

[0010] S1: Add the crude product of nicardipine hydrochloride to the first organic solvent, then heat it to dissolve, and then cool it down and keep it warm for crystal precipitation, filter, and dry under reduced pressure to obtain the acetonitrile solvate crystal form of nicardipine hydrochloride;

[0011] S2: Add the acetonitrile solvate crystal form of nicardipine hydrochloride to the second organic solvent, then heat it to dissolve, and then cool it down and keep it warm for crystal precipitation, filter, and dry under reduced pressure to obtain the high-quality product of α-crystal form of nicardipine hydrochloride.

[0012] Further, in step S1 of the present invention, the first organic solvent is one or more of acetonitrile, methanol, ethanol, and isopropanol, and preferably acetonitrile.

[0013] Further, in step S1 of the present invention, the temperature for cooling and crystal precipitation is 20-50 °C, preferably 20-45 °C, and more preferably 30 °C or 45 °C.

[0014] Further, in step S1 of the present invention, the duration for keeping warm and crystal precipitation is 6-10 h, preferably 6-8 h, and more preferably 8 h.

[0015] The present invention provides an acetonitrile solvate crystal form of nicardipine hydrochloride, which has characteristic peaks at 2θ angles of 11.30°±0.2°, 16.20°±0.2°, 17.66°±0.2°, 18.86°±0.2°, 20.28°±0.2°, 22.60°±0.2°, 24.12°±0.2°, 25.92°±0.2°, and 31.86°±0.2° in its X-ray powder diffraction pattern when using Cu-Kα radiation.

[0016] Further, the X-ray powder diffraction pattern of the nifedipine hydrochloride acetonitrile solvate crystal form is substantially as Figure 9 shown.

[0017] Further, the differential scanning calorimetry analysis pattern of the nifedipine hydrochloride acetonitrile solvate crystal form is as Figure 7 shown, and it has a maximum endothermic peak at 120.57 ± 3 °C.

[0018] Further, the thermogravimetric analysis pattern of the nifedipine hydrochloride acetonitrile solvate crystal form is as Figure 8 shown, and the weight loss in the range of 30 - 120 °C is about 2.8 - 5.0%, preferably 3.2%.

[0019] The nifedipine hydrochloride acetonitrile solvate crystal form described in the present invention can improve the solubility of the nifedipine hydrochloride compound as a specific crystal form during the process.

[0020] The nifedipine hydrochloride acetonitrile solvate crystal form described in the present invention has obvious benefits for the purification ability of the nifedipine hydrochloride compound as a specific crystal form during the purification process.

[0021] Further, the second organic solvent in step S2 of the present invention is acetone or ethanol, preferably acetone.

[0022] Further, the temperature for cooling and crystallization in step S2 of the present invention is 30 - 50 °C, preferably 30 -

[0023] 40 °C, and more preferably 30 °C.

[0024] Further, the duration of cooling and crystallization in step S2 of the present invention is 4 - 8 h, preferably 6 - 8 h, and more preferably 8 h.

[0025] According to some specific embodiments of the present invention, the method for refining the industrial preparation of nifedipine hydrochloride α crystal form includes the following steps:

[0026] S1: Add the crude nifedipine hydrochloride to an acetonitrile solvent, then heat it to dissolve, and then cool it to 30 or 45 °C, keep it warm for crystallization for 8 h, filter, and dry under reduced pressure to obtain the nifedipine hydrochloride acetonitrile solvate crystal form;

[0027] S2: Add the nifedipine hydrochloride acetonitrile solvate crystal form to an acetone solvent, then heat it to dissolve, and then cool it to 30 °C, keep it warm for crystallization for 8 h, filter, and dry under reduced pressure to obtain the refined nifedipine hydrochloride α crystal form.

[0028] Among them, the X-ray powder diffraction pattern of the nifedipine hydrochloride acetonitrile solvate crystal form is substantially as Figure 9 shown.

[0029] The differential scanning calorimetry (DSC) thermogram of the nifedipine hydrochloride acetonitrile solvate crystal form is as follows Figure 7 shown, and it has a maximum endothermic peak at 120.57 ± 3 °C.

[0030] The thermogravimetric analysis (TGA) thermogram of the nifedipine hydrochloride acetonitrile solvate crystal form is as follows Figure 8 shown, and the weight loss within the range of 30 - 114 °C is 3.2%.

[0031] The beneficial effects brought by the present invention are as follows:

[0032] (1) The present invention provides a new method for refining nifedipine hydrochloride α crystal form for industrial production. This method has the advantages of simple operation, energy conservation and consumption reduction, short production cycle, good equipment compatibility, easy scale-up, and is suitable for large-scale industrial production.

[0033] (2) The purity of the nifedipine hydrochloride α crystal form prepared by the present invention reaches over 99.7%, any single impurity is less than 0.10%, and the yield reaches over 90%. Both the quality and yield of the product have obvious competitiveness and have practical promotion and application value.

[0034] Obviously, based on the above content of the present invention, according to the common general technical knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0035] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be understood as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is the HPLC chromatogram of the crude nifedipine hydrochloride prepared in the preparation example;

[0037] Figure 2 It is the HPLC chromatogram of the first refined product obtained when the refining solvent is acetonitrile in the solvent screening experiment;

[0038] Figure 3 It is the HPLC chromatogram of the first refined product obtained when the refining solvent is tetrahydrofuran in the solvent screening experiment;

[0039] Figure 4 It is the HPLC chromatogram of the first refined product obtained when the refining solvent is ethanol:ethyl acetate = 1:1 (v / v) in the solvent screening experiment;

[0040] Figure 5It is the HPLC chromatogram of the first refined product obtained when the refined solvent is methanol:ethyl acetate = 1:2 (v / v) in the solvent screening experiment;

[0041] Figure 6 For the 1 HNMR spectrum of the nifedipine hydrochloride acetonitrile solvate in Example 1;

[0042] Figure 7 It is the DSC spectrum of the nifedipine hydrochloride acetonitrile solvate in Example 1;

[0043] Figure 8 It is the TG spectrum of the nifedipine hydrochloride acetonitrile solvate in Example 1;

[0044] Figure 9 It is the XRPD spectrum of the nifedipine hydrochloride acetonitrile solvate in Example 1;

[0045] Figure 10 It is the HPLC chromatogram of the nifedipine hydrochloride acetonitrile solvate in Example 2;

[0046] Figure 11 It is the HPLC chromatogram of the nifedipine hydrochloride acetonitrile solvate in Example 3;

[0047] Figure 12 It is the HPLC chromatogram of the nifedipine hydrochloride α-crystal form in Example 4;

[0048] Figure 13 It is the DSC spectrum of the nifedipine hydrochloride α-crystal form in Example 4;

[0049] Figure 14 It is the XRPD spectrum of the nifedipine hydrochloride α-crystal form in Example 4;

[0050] Figure 15 It is the HPLC chromatogram of the nifedipine hydrochloride α-crystal form in Example 4 (the crystallization temperature is 40 °C, and the other reaction conditions remain unchanged);

[0051] Figure 16 It is the HPLC chromatogram of the nifedipine hydrochloride α-crystal form in Example 4 (the crystallization temperature is 50 °C, and the other reaction conditions remain unchanged);

[0052] Figure 17 It is the HPLC chromatogram of the nifedipine hydrochloride acetonitrile solvate in Example 5;

[0053] Figure 18 It is the HPLC chromatogram of the nifedipine hydrochloride α-crystal form in Example 6;

[0054] Figure 19 It is the HPLC chromatogram of the nifedipine hydrochloride α-crystal form in Example 7. Detailed implementation manners

[0055] The present invention was completed based on the following discoveries of the inventors: In order to find a purification route suitable for large-scale industrial production of nicardipine hydrochloride α-crystal form, the inventors surprisingly found during the screening of a large number of single or mixed solvents that acetonitrile organic solvent can not only better remove the impurities contained in the crude nicardipine hydrochloride; moreover, acetonitrile and nicardipine hydrochloride can form a nicardipine hydrochloride acetonitrile solvate crystal form, which can not only improve the solubility of the nicardipine hydrochloride compound, but also has obvious benefits for the purification ability of the nicardipine hydrochloride compound. Based on the nicardipine hydrochloride acetonitrile solvate crystal form, the inventors continued to investigate the crystal precipitation solvent, temperature and time parameters in the reaction conditions for the second purification to prepare nicardipine hydrochloride α-crystal form, and finally found a purification route suitable for large-scale industrial production of nicardipine hydrochloride α-crystal form, which has the advantages of simple operation, energy saving and consumption reduction, short production cycle and good equipment compatibility.

[0056] In the following examples, where specific techniques or conditions are not indicated, they shall be carried out according to the techniques or conditions described in the literature in this field or according to the product specifications. The raw materials, reagents or devices used in the following examples can be obtained from conventional commercial channels or can be obtained by existing known methods without special instructions. The explanations of the abbreviations used in this application are as follows:

[0057] The structure of the compound was determined by nuclear magnetic resonance ( 1 HNMR). The nuclear magnetic resonance ( 1 HNMR) chemical shift (δ) is given in parts per million (ppm); the nuclear magnetic resonance (NMR) measurement was performed using a BRUKER AVANCEⅢ 400 MHz nuclear magnetic resonance spectrometer with tetramethylsilane (TMS) as the internal standard.

[0058] The HPLC chromatogram was measured using an Agilent 1260 InfinityⅡ liquid chromatograph. In this application, the HPLC purity was determined by the following method:

[0059]

[0060] XRPD: X-ray powder diffraction. The X-ray powder diffraction (XRD) test described in this application was collected using a DX-2700 powder diffractometer, and the specific parameters are as follows in the table:

[0061]

[0062]

[0063] DSC: Differential Scanning Calorimeter. The determination of differential scanning calorimetry (DSC) described in this application was collected using a DSC25 from TA Instruments, USA. The heating rate was 10 °C / min, the temperature range was 30 - 200 °C, and the nitrogen purge rate during the test was 50 mL / min.

[0064] TG: Thermogravimetric Analyzer. The determination of thermogravimetric analysis (TGA) described in this application was collected using a TGA55 from TA Instruments, USA. The heating rate was 10 °C / min, the temperature range was 30 - 200 °C, and the nitrogen purge rate during the test was 50 mL / min.

[0065] The determination of loss on drying was carried out according to General Chapter 0831, Section IV of the Chinese Pharmacopoeia 2020 edition.

[0066] In the following examples, nicardipine hydrochloride is sometimes labeled as Nicardipine, sometimes as API, and sometimes as M3.

[0067] Preparation Example: The preparation process of crude nicardipine hydrochloride is as follows:

[0068] Add 700 g of acetonitrile to a 1 L three-necked flask, and add 100 g of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid monomethyl ester, 55 g of starting material N-methyl-N-hydroxyethylbenzylamine, 70 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 30 g of triethylamine, and 10 g of 4-dimethylaminopyridine. Stir and heat to 65 - 75 °C and react for 5 hours. After the reaction is completed, transfer the reaction solution to a 5 L flask, cool to 0 - 10 °C, add 1 L of dichloromethane and 1 L of purified water, dropwise add hydrochloric acid to adjust the pH to 3 - 4, let it stand, separate the organic phase, and concentrate it under reduced pressure below 50 °C; add 500 mL of acetone to the concentrate, stir and crystallize at 20 - 30 °C for 6 hours, filter, and dry the solid under reduced pressure at 40 - 50 °C for 5 hours to obtain 140 g of crude nicardipine hydrochloride, with a yield of about 90% and a purity of 99.480% ( Figure 1 ). The structure identification data are as follows: 1 HNMR(400MHz DMSO-d6): δ2.29(s, 3H), δ2.34(s, 3H), δ2.56(s, 3H), δ3.29(m, 2H), δ3.57(s, 3H), δ4.42(m, 4H), δ5.00(s, 1H), δ7.43(m, 3H), δ7.51(m, 1H), δ7.61(m, 3H), δ7.94(s, 2H), δ9.36(s, 1H), δ11.05(s, 1H).

[0069] Solvent Screening Experiment:

[0070] The inventor of the present invention found that the refining methods of the prior art are not suitable for industrial production. The inventor tried to adopt other refining methods and added the crude nicardipine hydrochloride prepared in the above preparation example to different solvents to investigate the effect of removing impurities. The specific operation steps are as follows: Add the crude nicardipine hydrochloride to four solvents, namely acetonitrile, tetrahydrofuran, ethanol:ethyl acetate = 1:1 (v / v), and methanol:ethyl acetate = 1:2 (v / v), stir and heat until completely dissolved, stop heating, continue to stir and cool for crystallization, cool down to 30 °C, keep the temperature for crystallization for 8 h, filter, and dry under reduced pressure at 50 °C for 6 h to obtain the first refined product.

[0071] When screening the refining solvent, the inventor surprisingly found that compared with other refining solvents, the acetonitrile solvent not only has a better effect of removing impurities, but also has a higher product yield in the first refining; in addition, the inventor confirmed that acetonitrile and nicardipine hydrochloride can form a solvate crystal form of nicardipine hydrochloride in acetonitrile, and the solubility of this crystal form in acetonitrile or acetone also has great differences at different temperatures. Therefore, the high-quality product of nicardipine hydrochloride α crystal form can be obtained by the way of cooling crystallization using the solubility properties of this crystal form. The results of the first refining solvent screening are shown in Table 1 below:

[0072] Table 1 Results of impurity removal experiments in different refining solvent systems

[0073]

[0074] From the above results, it can be seen that when the refining solvent is acetonitrile, the purity and yield of the intermediate solvate of nicardipine hydrochloride in acetonitrile are the highest, indicating that the acetonitrile solvent has a better effect of removing impurities and improves the quality of the product. Therefore, the inventor used acetonitrile as the refining solvent to conduct the following experimental verification.

[0075] Example 1 Preparation of nicardipine hydrochloride acetonitrile solvate

[0076] Add 20 g of crude nicardipine hydrochloride to 130 g of acetonitrile, stir and heat to 80 °C until completely dissolved, stop heating, continue to stir and cool for crystallization, cool down to 30 °C, keep the temperature for crystallization for 8 h, filter, and dry under reduced pressure at 50 °C for 6 h to obtain 18.8 g of yellow crystalline powder solid, with a yield of 94.0% and a purity of 99.611% ( Figure 2 ).

[0077] The inventor characterized the structure of the above-prepared sample, and the nuclear magnetic hydrogen spectrum data thereof is as follows (see Figure 6 )

[0078] Table 2 1 H-NMR spectrum of nicardipine hydrochloride acetonitrile solvate

[0079]

[0080]

[0081] The obtained sample was subjected to differential scanning calorimetry (DSC) as Figure 7 shown. It had an endothermic melting peak in the range of 30 - 200 °C, with the peak value at 120.57 °C. The obtained sample was subjected to thermogravimetric analysis (TG) as Figure 8 shown. The weight loss in the range of 30 - 120 °C was 3.127%. The acetonitrile content of the crystalline sample was determined by loss on drying to be 3.2%. This crystal form was significantly different from the five previously reported crystal forms and was named nicardipine hydrochloride acetonitrile solvate.

[0082] X-ray powder diffraction was performed using Cu-Kα radiation, and its diffraction pattern had the diffraction angles, interplanar spacings, and relative intensities shown in the following table:

[0083] Table 3 Diffraction Angles, Interplanar Spacings, and Relative Intensities of Nicardipine Hydrochloride Acetonitrile Solvate

[0084] Peak No. Diffraction Angle 2θ Interplanar Spacing d Relative Intensity 1 7.92° 11.15 33.0 2 10.60° 8.34 52.1 3 11.30° 7.82 80.0 4 15.74° 5.62 25.8 5 16.20° 5.46 47.5 6 17.10° 5.18 26.2 7 17.66° 5.02 84.3 8 18.86° 4.70 74.7 9 20.28° 4.37 51.1 10 22.60° 3.93 53.6 11 24.12° 3.69 83.4 12 24.90° 3.57 49.0 13 25.40° 3.50 33.9 14 25.92° 3.43 100 15 26.50 3.36 32.6 16 27.40 3.25 25.3 17 29.36 3.04 42.7 18 31.86 2.80 51.3

[0085] Note: The error of the 2θ diffraction angle is ±0.20°.

[0086] Furthermore, the nicardipine hydrochloride acetonitrile solvate prepared in Example 1 had an X-ray powder diffraction pattern substantially as Figure 9 shown.

[0087] Example 2 Preparation of Nicardipine Hydrochloride Acetonitrile Solvate

[0088] 10 g of crude nicardipine hydrochloride was added to 50 ml of acetonitrile and 10 ml of methanol. The temperature was raised to 80 °C and stirred until completely dissolved. Then it was cooled to 20 °C and kept for 6 h for crystallization. After filtration, it was dried under reduced pressure at 50 °C for 4 h to obtain 6.2 g of a pale yellow crystalline powdery solid. The yield was 62.0% and the purity was 99.769% ( Figure 10 ). Its 1H NMR data, differential scanning calorimetry pattern, thermogravimetric analysis pattern, and powder diffraction data were substantially consistent with those of Example 1.

[0089] Example 3 Preparation of Nicardipine Hydrochloride Acetonitrile Solvate

[0090] 10 g of crude nicardipine hydrochloride was added to 55 ml of acetonitrile and 20 ml of ethanol. The temperature was raised to 80 °C and stirred until completely dissolved. Then it was cooled to 20 °C and kept for 6 h for crystallization. After filtration, it was dried under reduced pressure at 50 °C for 4 h to obtain 8.6 g of a pale yellow crystalline powdery solid. The yield was 86% and the purity was 99.806% ( Figure 11 ). Its 1H NMR data, differential scanning calorimetry pattern, thermogravimetric analysis pattern, and powder diffraction data were substantially consistent with those of Example 1.

[0091] Preparation of Nicardipine Hydrochloride α-Crystal Form in Example 4

[0092] 10 g of the nicardipine hydrochloride acetonitrile solvate obtained in Example 1 was added to 100 ml of acetone. The temperature was raised to 50 °C and stirred until completely dissolved. Then the temperature was lowered to 30 °C and kept for 8 h for crystallization. After filtration, it was dried under reduced pressure at 50 °C for 4 h to obtain 9.6 g of a pale yellow powder solid. The yield was 96%, and the purity was 99.752%( Figure 12 ).

[0093] Differential scanning calorimetry (DSC) was performed on the obtained sample as Figure 13 shown. It had an endothermic melting peak in the range of 30 - 200 °C, and the peak value was 190.28 °C;

[0094] X-ray powder determination was performed using Cu-Kα radiation, and its diffraction pattern had the diffraction angle, interplanar spacing, and relative intensity shown in the following table:

[0095] Table 4 Diffraction Angle, Interplanar Spacing, and Relative Intensity of Nicardipine Hydrochloride α-Crystal Form

[0096] Peak No. Diffraction Angle 2Θ Interplanar Spacing d Relative Intensity 1 8.14° 10.85 100 2 14.10° 6.27 24.7 3 16.06° 5.51 98.5 4 18.11° 4.89 35.5 5 20.32° 4.36 30.6 6 21.60° 4.11 45.3 7 24.74° 3.59 29.5 8 25.42° 3.50 20.0 9 32.92° 2.72 24.8

[0097] Note: The error of the 2θ diffraction angle is ±0.20°.

[0098] Furthermore, the nicardipine hydrochloride α-crystal form prepared in Example 4 had an X-ray powder diffraction pattern substantially as Figure 14 shown.

[0099] In addition, the inventors investigated the crystallization solvent, temperature, and time parameters in the reaction conditions for preparing the nicardipine hydrochloride α-crystal form by the second purification. Among them, the crystallization solvents acetone and ethanol were experimentally verified. It was found that when the nicardipine hydrochloride acetonitrile solvate was cooled for crystallization in ethanol, sudden crystallization occurred, and the obtained product was viscous in the solvent, making it impossible to discharge the material and difficult to filter, which was not suitable for industrial production; while using acetone as the purification solvent had the opposite effect. The following Table 5 shows the inventors' investigation of the crystallization temperature and duration for the second purification when the crystallization solvent was acetone.

[0100] Table 5 Influence of Crystallization Temperature and Time for the Second Purification

[0101]

[0102] Preparation of Scale-up Test of Nicardipine Hydrochloride Acetonitrile Solvate in Example 5

[0103] 150 kg of acetonitrile and 22.5 kg of crude nicardipine hydrochloride were added into a 300 L reactor. The temperature was raised to 80 °C and stirred until completely dissolved. Then the temperature was lowered to 45 °C and crystallization was carried out while maintaining the temperature for 8 h. After filtration, drying was carried out under reduced pressure at 50 °C for 4 h to obtain 21.4 kg of a yellow crystalline powder solid. The yield was 95.1%, and the purity was 99.933%( Figure 17 ). Its 1H NMR data, differential scanning calorimetry (DSC) pattern, thermogravimetric analysis (TGA) pattern, and powder diffraction data were basically consistent with those of Example 1.

[0104] Preparation of α-crystal form of nicardipine hydrochloride in Example 6 for scale-up experiment

[0105] 200 kg of acetone and 20.0 kg of acetonitrile solvate of nicardipine hydrochloride were added into a 300 L reactor. The temperature was raised to 50 °C and stirred until completely dissolved. Then the temperature was lowered to 30 °C and crystallization was carried out while maintaining the temperature for 8 h. After filtration, drying was carried out under reduced pressure at 50 °C for 4 h to obtain 18.4 kg of a light yellow powder solid. The yield was 92.0%, and the purity was 99.946%( Figure 18 ). Its DSC pattern and powder diffraction data were basically consistent with those of Example 4.

[0106] Preparation of α-crystal form of nicardipine hydrochloride by the purification method of Patent JPH03240773A in Example 7

[0107] 20 g of crude nicardipine hydrochloride was added into 60 g of methanol. The mixture was stirred and heated to 60 °C until completely dissolved. Heating was stopped, and methanol was removed by vacuum distillation until dry to obtain a foamy solid. 200 g of acetone was added to this solid, and crystallization was carried out while maintaining the temperature at 30 °C for 8 h. After filtration, drying was carried out under reduced pressure at 50 °C for 4 h to obtain 17.0 g of a light yellow powder solid. The yield was 85%, and the purity was 99.560%( Figure 19 ). Its DSC pattern and powder diffraction data were basically consistent with those of Example 4.

[0108] Comparison of solubility and purity data in Example 8

[0109] The solubilities of the acetonitrile solvate of nicardipine hydrochloride and the α-crystal form of nicardipine hydrochloride prepared in Example 1 and Example 7 respectively were compared, and the comparison results are shown in Table 6:

[0110] Table 6 Comparison results of solubility

[0111]

[0112] Table 6 above shows that the solubility of nicardipine hydrochloride acetonitrile solvate varies with temperature in acetone and acetonitrile solvents. Therefore, the nicardipine hydrochloride α-crystal can be directly prepared by heating and dissolving the nicardipine hydrochloride acetonitrile solvate crystal form and then crystallizing by cooling. This method greatly reduces the operation steps and time, and saves the production cost.

[0113] The purities of the nicardipine hydrochloride acetonitrile solvate and nicardipine hydrochloride α-crystal prepared in Example 1, Example 3, Example 6 and Example 7 were compared respectively, and the comparison results are shown in Table 7:

[0114] Table 7 Comparison results of purities

[0115]

[0116] Table 7 above shows that by adopting the technical solution of the present invention, a large amount of impurities can be effectively removed during the first purification process of preparing nicardipine hydrochloride acetonitrile solvate, improving the product quality. During the second purification process of preparing nicardipine hydrochloride α-crystal, while further removing impurities, the nicardipine hydrochloride acetonitrile solvate can be prepared into a high-purity nicardipine hydrochloride α-crystal.

[0117] The above-described embodiments are merely descriptions of the preferred embodiments of the present invention, and do not limit the scope of the present invention. Without departing from the design spirit of the present invention, various deformations and improvements made by those of ordinary skill in the art to the technical solution of the present invention shall fall within the protection scope determined by the claims of the present invention.

Claims

1. A refining method for the industrial preparation of nicardipine hydrochloride α-crystal form, characterized in that, It includes the following steps: S1: Add the crude nicardipine hydrochloride to the first organic solvent, then heat it up to dissolve, then cool it down and keep the temperature for crystallization, filter, and dry under reduced pressure to obtain the acetonitrile solvate crystal form of nicardipine hydrochloride; S2: Add the acetonitrile solvate crystal form of nicardipine hydrochloride to the second organic solvent, then heat it up to dissolve, then cool it down and keep the temperature for crystallization, filter, and dry under reduced pressure to obtain the high-quality α crystal form of nicardipine hydrochloride.

2. The refining method according to claim 1, characterized in that, In step S1, the first organic solvent is one or more of acetonitrile, methanol, ethanol, and isopropanol, preferably acetonitrile.

3. The refining method according to claim 1, characterized in that, In step S1, the temperature for cooling crystallization is 20 - 50 °C, preferably 20 - 45 °C, more preferably 30 °C or 45 °C.

4. The refining method according to claim 1, characterized in that, In step S1, the duration for keeping the temperature for crystallization is 6 - 10 h, preferably 6 - 8 h, more preferably 8 h.

5. The refining method according to claim 1, characterized in that, For the acetonitrile solvate crystal form of nicardipine hydrochloride in step S1, under the condition of using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 11.30° ± 0.2°, 16.20° ± 0.2°, 17.66° ± 0.2°, 18.86° ± 0.2°, 20.28° ± 0.2°, 22.60° ± 0.2°, 24.12° ± 0.2°, 25.92° ± 0.2°, 31.86° ± 0.2°.

6. The refining method according to claim 1, characterized in that, The X-ray powder diffraction pattern of the acetonitrile solvate crystal form of nicardipine hydrochloride in step S1 is basically as shown in Figure 9.

7. The refining method according to claim 1, characterized in that, The differential scanning calorimetry spectrum and thermogravimetric analysis spectrum of the acetonitrile solvate crystal form of nicardipine hydrochloride in step S1 are basically as shown in Figures 7 and 8 respectively.

8. The refining method according to claim 1, characterized in that, In step S2, the second organic solvent is acetone or ethanol, preferably acetone.

9. The refining method according to claim 1, characterized in that, In step S2, the temperature for cooling crystallization is 30 - 50 °C, preferably 30 - 40 °C, more preferably 30 °C.

10. The refining method according to claim 1, characterized in that, In step S2, the duration for cooling crystallization is 4 - 8 h, preferably 6 - 8 h, more preferably 8 h.

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